For granulating powders, methods are known, for example the extrusion method, crushing method, spraying method, rolling method and fluidized-bed method. In granulating powders by these methods, a binder is generally used for intensifying the bonding among powder particles. In adding such a binder, an organic solvent or water is generally used. Thus, a solution of the binder in said organic solvent or water is added to said powder or, alternatively, the binder is added, in its powder form, to said powder, followed by addition of a solvent.
However, the use of organic solvents causes problems from the viewpoints of working environment, air pollution, safety and health, among others. On the other hand, the use of water makes it difficult to stably granulate compositions containing a medicinal substance which can be readily inactivated by water, for example a protein or antibiotic.
Among the granulation methods mentioned above, extrusion methods and crushing methods can granulate without using any solvent. However, the extrusion granulation method involves melting of the powders and the heat applied may readily inactivate the medicinal substances contained therein. This limits the range of application of said method. The granulation method essentially comprising crushing gives a broad grain size distribution to the granulated preparations and at the same time leads to dust (fine powder) formation. Furthermore, the granulated preparations produced by the crushing method have uneven grain surfaces and therefore, with them, it is difficult to achieve uniform coating, in particular uniform enteric coating.
On the other hand, with regard to the fluidized-bed granulation method, Japanese Patent laid open No. 34780/1973 discloses a granulation method which comprises fluidizing and heating a mixture of a plasticizable powder binder and an ingredient to be granulated, in a fluidized-bed reactor for causing adhesion or aggregation of said ingredient to or on the binder particle surface that has become sticky as a result of heating. Japanese Patent laid open No. 214333/1983 discloses granulated preparations produced by heating a mixture of a powder and a powdery/granular low-melting substance in a fluidized state for causing adhesion of the powder to the low-melting substance in the process of melting thereof. Japanese Patent Publication No. 20571/1979 discloses a method of granulating a powder tablet ingredient which comprises admixing the tablet ingredient with a powdery binder capable of melting or softening at a temperature inert to said ingredient, heating the resulting mixture in a fluidized bed at a temperature not lower than the melting point of the binder and then cooling the mixture to a temperature lower than the melting point of the binder without interrupting the air stream in the fluidized bed. These methods can give granulated preparations with relatively smooth surfaces in good yields in a solvent-free system without any step of crushing.
Japanese Patent laid open No. 56577/1973 discloses a method of producing granulated preparations with an average grain size of 20-60 mesh which comprises preparing pellet grains, 2-10 mm in diameter, in a dry state using 1 part by weight of a powdery carrier having a melting point of 45.degree.-100.degree. C. and 1-9 parts by weight of an active ingredient or an active ingredient-containing powder and crushing the resulting pellet grains at a temperature lower than the melting point of the powdery carrier by 5.degree. to 25.degree. C. using a crusher equipped with a knife rotating at a high speed. This method can give granulated preparations by utilizing the frictional heat generated on the occasion of pellet granulated preparation for melting the powdery carrier to thereby cause aggregation of the active ingredient, without severe dust formation.
Furthermore, Japanese Patent laid open No. 6869/1976 discloses a method of producing grains which comprises, in producing grains by drying and processing a mixture composed of a basic powdery substance and a meltable embedding substance under heating, causing said mixture to aggregate in a fluid mixer at a temperature not higher than the melting point of said embedding substance or at a temperature slightly higher than said melting point. In this method, the surface of the meltable embedding substance is rendered sticky by utilizing the actions of collision and friction as exerted on said meltable embedding substance in the step of mixing the mixture in the fluid mixer, whereby the basic powdery substance is allowed to aggregate on said surface without applying any external heat.
However, drug-containing granulated preparations produced by using those binders or low-melting substances that are described in the prior art documents cited above tend to show decreased drug dissolution or release due to the crystal polymorphism which the binders or the like exhibit. Furthermore, the drugs are readily inactivated upon interaction between the drugs and the binders and the like, hence the drugs cannot be stabilized for a prolonged period of time. Not only drugs but also various active ingredient-containing powders encounter these problems.